The long-term objectives of this ancillary application are to characterize a subpopulation of smokers with auto-reactive T cell response, to validate immunodiagnostic assays that could detect emphysema, and to find molecular signatures for pathogenic T cell development in a well-characterized cohort participating in SPROMICS (UCSF center). One of the major medical challenges facing us is that susceptibility to smoking-induced lung diseases varies greatly and essentially precludes our ability to predict which smokers will develop emphysema. Because the SPIROMICS study is designed to phenotype a large and heterogeneous group of smokers, we have chosen this cohort to identify the subpopulation who have auto-reactive T cells, as this may represent a contributing mechanism in the development of emphysema, which may need alternative therapies, and may represent a group of patients who will have progressive disease despite smoking cessation.
In Aim 1, we will prospectively determine the presence of auto-reactive T cell responses as determined by increased cytokine release in 180 ever-smokers with and without emphysema;
in Aim 2 we will focus on the longitudinal aspect of the factors that could predispose development of auto-reactive T cells in the population at risk. These studies form the prerequisite basis for developing additional novel immune-based diagnostic and therapeutic strategies in human emphysema. The short-term objectives outlined here are based on our preliminary data, and provide the necessary platform that will be used to answer the following urgent questions: i) in a distinct prospective cohort of ever smokers, can auto-reactive T cells predict the presence of radiographic emphysema? ii) Can we identify unique and persistent transcriptional signature(s) that are associated with autoimmune emphysema? The observational and longitudinal design of SPIROMICS allows for detailed assessment of the association between emphysema as the primary clinical endpoints and could validate the novel T cell specific immunodiagnostic potential that has been developed in our laboratory. We propose to explore the role of autoimmunity as a contributing mechanism in the development of emphysema with the additional aim of bringing current technologies to bear on clinical and future diagnostic tests.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Punturieri, Antonello
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Baylor College of Medicine
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Gu, Bon-Hee; Madison, Matthew C; Corry, David et al. (2018) Matrix remodeling in chronic lung diseases. Matrix Biol 73:52-63
Liu, Yanhong; O'Brien, Jacqueline L; Ajami, Nadim J et al. (2018) Lung tissue microbial profile in lung cancer is distinct from emphysema. Am J Cancer Res 8:1775-1787
Tung, Hui-Ying; Landers, Cameron; Li, Evan et al. (2016) Allergen-encoded signals that control allergic responses. Curr Opin Allergy Clin Immunol 16:51-8
Liu, Yanhong; Kheradmand, Farrah; Davis, Caleb F et al. (2016) Focused Analysis of Exome Sequencing Data for Rare Germline Mutations in Familial and Sporadic Lung Cancer. J Thorac Oncol 11:52-61
Bhavani, Sivasubramanium; Tsai, Chu-Lin; Perusich, Sarah et al. (2015) Clinical and Immunological Factors in Emphysema Progression. Five-Year Prospective Longitudinal Exacerbation Study of Chronic Obstructive Pulmonary Disease (LES-COPD). Am J Respir Crit Care Med 192:1171-8
Strange, Charlie; Senior, Robert M; Sciurba, Frank et al. (2015) Rationale and Design of the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis Study. Alpha-1 Protocol. Ann Am Thorac Soc 12:1551-60
Moller, David R; Koth, Laura L; Maier, Lisa A et al. (2015) Rationale and Design of the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) Study. Sarcoidosis Protocol. Ann Am Thorac Soc 12:1561-71
Bhavani, Sivasubramanium; Yuan, Xiaoyi; You, Ran et al. (2015) Loss of Peripheral Tolerance in Emphysema. Phenotypes, Exacerbations, and Disease Progression. Ann Am Thorac Soc 12 Suppl 2:S164-8
Lu, Wen; You, Ran; Yuan, Xiaoyi et al. (2015) The microRNA miR-22 inhibits the histone deacetylase HDAC4 to promote T(H)17 cell-dependent emphysema. Nat Immunol 16:1185-94
Liu, Jian; Cho, Sung-Nam; Akkanti, Bindu et al. (2015) ErbB2 Pathway Activation upon Smad4 Loss Promotes Lung Tumor Growth and Metastasis. Cell Rep :

Showing the most recent 10 out of 11 publications